Regulation of CD40 signaling in colon cancer cells and its implications in clinical tissues

Zhou, Yan; Zhou, Shuxian; Gao, Long; Li, Xiao-an

doi:10.1007/s00262-016-1847-0

Cited by 11 publications

(10 citation statements)

References 19 publications

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“…In human colorectal cancer tissue, AhRR expression correlated with CD40/CD40L signaling and histological grade. Subsequent experiments in colon cancer cell-lines revealed that CD40L treatment increases AhRR expression, resulting in a more pronounced inhibition of tumor cell growth and induction of apoptosis, respectively (80). Like other members of the tumor necrosis factor (TNF) receptor family, CD40 activation induces nuclear translocation and DNA-binding of RelB/p50 (81), which may contribute to proper anti-tumor immune responses (82), for instance in colorectal cancer (83).…”

Section: The Ahrr In Cancer Biologymentioning

confidence: 99%

The aryl hydrocarbon receptor repressor – More than a simple feedback inhibitor of AhR signaling: Clues for its role in inflammation and cancer

Vogel

Haarmann‐Stemmann

2017

Current Opinion in Toxicology

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The aryl hydrocarbon receptor repressor (AhRR) was first described as a specific competitive repressor of aryl hydrocarbon receptor (AhR) activity based on its ability to dimerize with the AhR nuclear translocator (ARNT) and through direct competition of AhR/ARNT and AhRR/ARNT complexes for binding to dioxin-responsive elements (DREs). Like AhR, AhRR belongs to the basic Helix-Loop-Helix/Per-ARNT-Sim (bHLH/PAS) protein family but lacks functional ligand-binding and transactivation domains. Transient transfection experiments with ARNT and AhRR mutants examining the inhibitory mechanism of AhRR suggested a more complex mechanism than the simple mechanism of negative feedback through sequestration of ARNT to regulate AhR signaling. Recently, AhRR has been shown to act as a tumor suppressor gene in several types of cancer cells. Furthermore, epidemiological studies have found epigenetic changes and silencing of AhRR associated with exposure to cigarette smoke and cancer development. Additional studies from our laboratories have demonstrated that AhRR represses other signaling pathways including NF-κB and is capable of regulating inflammatory responses. A better understanding of the regulatory mechanisms of AhRR in AhR signaling and adverse outcome pathways leading to deregulated inflammatory responses contributing to tumor promotion and other adverse health effects is expected from future studies. This review article summarizes the characteristics of AhRR as an inhibitor of AhR activity and highlights more recent findings pointing out the role of AhRR in inflammation and tumorigenesis.

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Section: The Ahrr In Cancer Biologymentioning

confidence: 99%

The aryl hydrocarbon receptor repressor – More than a simple feedback inhibitor of AhR signaling: Clues for its role in inflammation and cancer

Vogel

Haarmann‐Stemmann

2017

Current Opinion in Toxicology

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“…TOGARAM1 encodes a TOG domain array-containing protein that regulates the structure of cilia microtubules (54). apoptosis (56), angiogenesis (57), tumor cell migration and invasion (58), and chemoresistance (59) are unknown. Agonist CD40 antibodies have been developed and tested in clinical trials, in which impressive results have been noted, especially in pancreatic cancer (60).…”

Section: Discussionmentioning

confidence: 99%

“…CD40 belongs to the TNF receptor family and is crucial to the mediation of a variety of immune and inflammatory responses [55]. CD40 ligation provides essential activation signals for immune cells [55], although its function in the promotion or inhibition of tumorigenesis and progression via regulation of TNF alpha (TNFα)‐induced apoptosis [56], angiogenesis [57], tumor cell migration and invasion [58], and chemoresistance [59] is unknown. Agonist CD40 antibodies have been developed and tested in clinical trials, in which impressive results have been noted, especially in pancreatic cancer [60].…”

Section: Discussionmentioning

confidence: 99%

A methylation‐driven gene panel predicts survival in patients with colon cancer

et al. 2021

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The accumulation of various genetic and epigenetic changes in colonic epithelial cells has been identified as one of the fundamental processes that drive the initiation and progression of colorectal cancer (CRC). The present study aimed to explore functional genes regulated by DNA methylation, and their potential utilization as biomarkers for the prediction of CRC prognoses. Methylation-driven genes (MDGs) were explored by applying the integrative analysis tool (MethylMix) to the Cancer Genome Atlas (TCGA) CRC project. The prognostic MDG panel was identified by combining the Cox regression model with the least absolute shrinkage and selection operator regularization. Gene set enrichment analysis was utilized to determine the pathways associated with the 6-MDG panel. CD40 expression and methylation in CRC samples was validated by using additional datasets from the Gene Expression Omnibus. Methylation-specific PCR and bisulfite sequencing were used to confirm DNA methylation in CRC cell lines. A prognostic MDG panel consisting of six gene members was identified: TMEM88, HOXB2, FGD1, TOGARAM1, ARHGDIB, and CD40. The high-risk phenotype classified by the 6-MDG panel was associated with cancer-related biological processes, including invasion and metastasis, angiogenesis, and the tumor immune microenvironment. The prognostic value of the 6-MDG panel was found to be independent of TNM stage, and in combination with TNM stage and age could help improve survival prediction. Additionally, the expression of CD40 was confirmed to be regulated by promoter region methylation in CRC samples and cell lines. The proposed 6-MDG panel represents a promising signature for estimating the prognosis of patients with CRC.

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“…CD40 belongs to the family of TNF receptors and is crucial in mediating a variety of immune and in ammatory responses [55]. CD40 ligation provides essential activation signals for immune cells [55], while CD40 possesses controversial functions in promoting or inhibiting tumorigenesis and progression via regulation of TNFα-induced apoptosis [56], angiogenesis [57], tumor cell migration and invasion [58] and chemoresistance [59]. Agonist CD40 antibodies have been developed and tested in clinical trials where impressive results have been noted, especially in pancreatic cancers [60].…”

Section: Discussionmentioning

confidence: 99%

Identification of a Methylation-Driven Gene Panel for Survival Prediction in Colon Cancer

Peng

Zhao

Yin

et al. 2020

Preprint

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Background: Prediction and improvement of prognosis is important for effective clinical management of colon cancer patients. Accumulation of a variety of genetic as well as epigenetic changes in colon epithelial cells has been identified as one of the fundamental processes that drive the initiation and progression of colon cancer. This study aimed to explore functional genes regulated by DNA methylation and the potential of these DNA methylation changes to become biomarkers predictive of colon cancer prognosis.Methods: Methylation-driven genes (MDGs) were explored by applying an integrative analysis tool (MethylMix) to The Cancer Genome Atlas (TCGA) colon cancer project. TCGA colon cancer patients with available survival information (n=281) were randomly divided into training dataset (50%) for model construction and testing dataset (50%) for model validation. The prognostic MDG panel was identified in the training dataset by combining the Cox regression model with the least absolute shrinkage and selection operator regularization, a widely used approach to penalize the effect of multicollineatity. GSEA was employed to determine functional pathways associated with the prognostic 6-MDG panel. CD40 expression and methylation in colon cancer samples were also examined in datasets (expression profile [GSE8671] and methylation profile [GSE42752]) from Gene Expression Omnibus. Experimental confirmation of DNA methylation in colon cancer cell lines was performed using methylation specific PCR and bisulfite sequencing.Results: We identified and internal validated a prognostic methylation-driven gene panel consisting of six gene members (TMEM88, HOXB2, FGD1, TOGARAM1, ARHGDIB and CD40). High risk phenotype classified by the 6-MDGs panel was associated with cancer-related biological processes, including invasion and metastasis, angiogenesis and tumor immune microenvironment, among others. The prognostic value of the 6-MDGs panel was independent of TNM stage, and its combination with TNM stage and age could help improve survival prediction of colon cancer patients. Additionally, we validated that the expression of CD40 was regulated by promoter region methylation in colon cancer samples and cell lines. Conclusions: The proposed 6-MDGs panel represents a promising signature for estimating overall survival in patients with colon cancer.

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Regulation of CD40 signaling in colon cancer cells and its implications in clinical tissues

Cited by 11 publications

References 19 publications

The aryl hydrocarbon receptor repressor – More than a simple feedback inhibitor of AhR signaling: Clues for its role in inflammation and cancer

The aryl hydrocarbon receptor repressor – More than a simple feedback inhibitor of AhR signaling: Clues for its role in inflammation and cancer

A methylation‐driven gene panel predicts survival in patients with colon cancer

Identification of a Methylation-Driven Gene Panel for Survival Prediction in Colon Cancer

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